Smoke inhalation and burn injury induce an inflammatory pneumonitis that may progress to severe respiratory failure. Current treatment options are limited to supportive measures. We propose to test the feasibility of a revolutionary anti-inflammatory approach in the management of smoke inhalation induced acute lung injury (ALI). A recently discovered mechanism of inflammatory injury, the "Poly (ADP-ribose) Synthetase (PARS) Pathway", has been implicated in the pathogenesis of inflammatory injury. Triggered by oxidant-induced DNA single strand breaks, PARS catalyzes an energy-consuming polymerization of ADP- ribose, resulting in NAD depletion, inhibition of glycolysis and mitochondrial respiration, and the ultimate reduction of intracellular high energy phosphates. PARS activation also strongly upregulates expression of pro-inflammatory cytokines, chemokines, and adhesion molecules. The administration of PARS inhibitors has been shown to have a protective effect in experimental models of inflammation and altered blood flow, including arthritis, stroke, and endotoxic shock. The central objective of this grant proposal is to establish that Inotek's lead PARS inhibitor, PJ-34, improves hemodynamics, end-organ injury, and oxygenation in an ovine model of thermal injury induced ALI. After smoke inhalation and burn injury, sheep will be treated with PJ-34 (3-30 mg/kg i.v.). The percent change from baseline pulmonary vascular resistance, systemic vascular resistance, cardiac output, and PaO2/FiO2 ratio will be compared to untreated controls. At 48 h, we will measure the effect of PJ-34 on a comprehensive series of inflammatory indices of lung injury to assess lipid peroxidation, neutrophil infiltration, histology, and peroxynitrite formation. We will correlate the efficacy of PJ-34 with its serum concentration, in order to create a pharmacodynamic profile. We expect that PJ-34 will dose-dependently reduce lung inflammation and injury in this clinically relevant model of combined smoke inhalation and burn injury. PROPOSED COMMERCIAL APPLICATIONS: The annual domestic impact of burn injury and smoke inhalation induced ALI on the health care market is estimated at > $50 million. The worldwide market (developed countries only) is four times larger. Given the absence of a specific, safe, and convenient existing therapy, Inotek anticipates market acceptance to be achieved rapidly, at high levels of penetration, and with a high sustained price point ($1000 per patient). Estimated worldwide gross sales revenues after market entry and maturation (ca. 4 years after FDA approval) equal $250 million (annual).